Abstract
Lung cancer is the most common cause of cancer mortality worldwide. Non-small-cell lung carcinomas (NSCLCs), which represent around 80% of lung tumors, exhibit poor prognosis and are usually refractory to conventional chemotherapy. Elucidating the molecular and cellular mechanisms that are dysregulated in NSCLCs may lead to new possibilities for targeted therapy or enhanced efficacy of current therapies. Here we demonstrate Wnt pathway activation in around 50% of human NSCLC cell lines and primary tumors, through different mechanisms, including autocrine Wnt pathway activation involving upregulation of specific Wnt ligands. Downregulation of activated Wnt signaling inhibited NSCLC proliferation and induced a more differentiated phenotype. Together, our findings establish importance of activated Wnt signaling in human NSCLCs and offer the possibility of targeting upregulated Wnt signaling as a new therapeutic modality for this disease.
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Acknowledgements
This work was supported by grant number 5R01CA071672 from the National Cancer Institute. SV is supported by consecutive post-doctoral fellowships from New York State Department of Health and American Urological Association. We are grateful to Dr J Minna and Dr A Gazdar (University of Texas Southwestern Medical Center, Dallas, TX, USA) for providing us with some NSCLC cell lines. We thank Dr Stefano Rivella (Weill Medical College of Cornell University, New York, NY, USA) for the generous gift of the lentiviral vector, pRRL-SIN-cPPT-PGK-GFP. We also thank Dr Robert Hannigan (Mount Sinai School of Medicine, New York, NY, USA) and Professor Roger Tsien (Howard Hughes Medical Institute, University of California, San Diego, CA, USA) for kindly providing us with the cDNA encoding mOrange. We especially thank Randy Arroyave for excellent technical assistance and Martina Kracikova and Ioana Rus for critical reading of this paper.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
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Akiri, G., Cherian, M., Vijayakumar, S. et al. Wnt pathway aberrations including autocrine Wnt activation occur at high frequency in human non-small-cell lung carcinoma. Oncogene 28, 2163–2172 (2009). https://doi.org/10.1038/onc.2009.82
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DOI: https://doi.org/10.1038/onc.2009.82
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